Chemoenzymatic Total Synthesis of Sorbicatechol Structural Analogues and Evaluation of Their Antiviral Potential

Abstract

Sorbicillinoids are fungal polyketides characterized by highly complex and diverse molecular structures, with considerable stereochemical intricacy combined with a high degree of oxygenation. Many sorbicillinoids possess promising biological activities. An interesting member of this natural product family is sorbicatechol A, which is reported to have antiviral activity, particularly against influenza A virus (H1N1). Through a straightforward, one‐pot chemoenzymatic approach with recently developed oxidoreductase SorbC, the characteristic bicyclo[2.2.2]octane core of sorbicatechol is structurally diversified by variation of its natural 2‐methoxyphenol substituent. This facilitates the preparation of a focused library of structural analogues bearing substituted aromatic systems, alkanes, heterocycles, and ethers. Fast access to this structural diversity provides an opportunity to explore the antiviral potential of the sorbicatechol family.

Evaluation of the Substrate Promiscuity of SorbC for the Chemo-Enzymatic Total Synthesis of Structurally Diverse Sorbicillinoids

“…A number of different derivatives 13 – 22 were thus readily available in just one synthetic step (8–72%). The ester analogues of sorbicillin, 23 and 24 , were synthesized by carboxylation of 9 with subsequent ester formation, as described previously . The R 3 -substituted sorbicillins 25 – 30 were prepared from 1,3-dimethoxybenzene ( 10 ).…”

“…The dienophiles intercepted by 2 mostly differ in the alkene substitution pattern. The saturnisols (C, D) and antiviral sorbicatechols (against H1N1, A: IC 50 = 85 μM, B: IC 50 = 113 μM) , belong to a class of compounds derived of a Diels–Alder reaction of hydroxy-/sorbicillinol with a monosubsituted alkenes, e.g., styrene for saturnispol C ( 6 ). In the case of cyclic disubstituted alkene reaction partners, tricyclic sorbicillinoids, e.g., trichosorbicillin A ( 8 ), can be formed.…”

“…The ester analogues of sorbicillin, 23 and 24, were synthesized by carboxylation of 9 with subsequent ester formation, as described previously. 12 The R 3 -substituted sorbicillins 25−30 were prepared from 1,3dimethoxybenzene (10). Ortho-directed lithiation in the first step allowed for the installation of the desired alkyl group using the corresponding alkyl iodide as electrophile.…”

“…This compound is closely related to the sorbicatechols, 11 which are all formed with perfect endo selectivity in the Diels−Alder reaction. This can be deduced from 1 H-NMR chemical shifts, 12 especially at position H-7 (6: δ = 1.89, 3.04; 7: δ = 1.84, 3.05). Subsequent use of the same substrates as for the bisorbicillinol analogues above provided the hybrid sorbicatechols 49 (15% yield), 50 (14%), 51 (24%), 52 (14%), and 53 (31%).…”

Catalytic Enantioselective Diels Alder Reaction: Application in the Synthesis of Antiviral Agents

“…Using the Nicolaou words, the DAR has afforded numerous and unparalleled solutions to a diverse range of synthetic puzzles provided by nature in the form of natural products [49]. Even if there are several examples of the application of this reaction applied to natural compounds endowing antiviral activity-referred, for example, to anti-influenza (-)-Cytisine derivatives [77] and Sorbicatechol [78] to the Anti-HIV agent Siamenol [79] herein we report one selected example in which the asymmetric DAR protocol was applied, using chiral diene in the presence of LA to the synthesis of anti-influenza wickerol.…”